Vascular endothelial growth factor [VEGF; also known as vascular permeability factor (VPF)] is a highly conserved, potent multifunctional cytokine. Abnormal levels of production and or secretion of VEGF have been linked to a number of pathological conditions. For example, high concentrations of biologically active VEGF have been detected in pleural fluids and ascites of cancer patients (Zebrowski et al., 1999a, b).
Ascites, the accumulation of fluid in the abdominal cavity, may result from a number of conditions, including tumours and other disease states such as chronic liver disease. Cirrhosis of the liver is responsible for the majority of cases of ascites and the prognosis is generally poor.
Accumulation of malignant ascites is an important cause of morbidity and mortality in patients with peritoneal carcinomatosis. Causes of malignant ascites formation include colon, gastric, pancreatic, endometrial and ovarian cancer (Smith and Jayson, 2003). For example, the malignant progression of ovarian cancer is predominantly confined to the peritoneal cavity and often evolves to an ascites form (Ozols et al., 1980). Both tumour size and the accumulation of ascites are inversely associated with survival (Hasumi et al., 2002). Current therapeutic treatment of patients with advanced ovarian cancer associates cytoreductive surgery and systemic chemotherapy, the combination of paclitaxel and cisplatin being considered the initial chemotherapy for stage III and IV (Burbridge et al., 1999). However two thirds of patients already have advanced disease when diagnosed, and poor prognoses are associated with rapidly accumulating ascites fluid and highly invasive and pleomorphic cellular phenotypes. There remains a need for an effective method for the treatment of ascites and ascites-associated conditions.
Ascites is linked to peritoneal, as well as tumour microvascular hyperpermeability and several studies have implicated a role for VEGF in ascites formation via increasing vascular permeability. More generally, VEGF exerts a number of important effects on vascular endothelium including inducing new vascular formation. VEGF possesses potent vascular permeability-enhancing activity and abnormal levels of VEGF production or secretion lead to microvascular hyperpermeability. VEGF is now recognized as a key factor required for growth of tumours and is involved in many other disease states such as diabetes, arthritis including rheumatoid arthritis, psoriasis, endometriosis, cerebral oedema, atheroscelrosis, ischaemic heart disease, and retinopathic diseases such as age related macular degeneration.
Tumour secretion of VEGF is essential for ascites accumulation. Tumour cells usually represent the main source of VEGF, but tumour-associated stroma is also an important site of VEGF production. Blocking VEGF production or secretion by tumour cells, for example using a VEGF inhibitor, has been shown in animal studies to result in inhibition of ascites formation (Zebrowski et al., 1999a, b; Xu et al., 2000). There is also growing evidence that VEGF production and secretion is not limited to solid tumours, but that VEGF and VEGF receptors are expressed by a variety of leukemias and other haematological malignancies.
Accordingly, VEGF is an attractive target for therapeutic intervention and several strategies to block VEGF activity have been sought, including monoclonal antibodies, VEGF receptor antagonists, tyrosine kinase antagonists and soluble VEGF receptors (VEGF-trap). There remains a need however for an effective method of inhibiting VEGF production and/or secretion and for treatment of conditions associated with VEGF production and/or secretion.
The present invention is predicated on the inventors' surprising finding that the benzimidazole carbamate albendazole has a potent effect on VEGF levels secreted by human ovarian cancer cells in vitro and on VEGF levels in vivo, and exhibits significant inhibitory effect on a number of conditions associated with abnormal VEGF levels.